Role of angiotensin II in aging

Figures

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  Figure 1. Involvement of RAS peptides and receptors in aging regulation. The classical RAS positively regulates the induction of aging by activating AT1R. In contrast, AT2R is regarded as a counterbalance to AT1R-mediated aging. PRR is a new member of the RAS receptors and mediates aging (Yoshida et al., 2019). Ang-(1–7) binds to MAS to counter-regulate of AT1R-mediated aging. However, the roles that Ang-(1–7) receptor MrgD and Ang IV receptor AT4R play in aging remain unclear. ACE, angiotensin-converting enzyme; ACE2, angiotensin converting enzyme 2; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AT1R, angiotensin type I receptor; AT2R, angiotensin type 2 receptor; AT4R, angiotensin type 4 receptor; MrgD, Mas-related-G protein-coupled receptor; PRR, (pro)renin receptor; NO, nitric oxide.

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  Figure 2. Schematic representation of major sources of free radicals in the body and the consequences of free radical damage. Ang II not only produces ROS by activating Nox and favoring eNOS uncoupling, but also has a direct action on mtROS production. The oxidative stress in turn can damage macromolecules, such as proteins, lipids, and DNA, therefore resulting in tissue damage and aging. ROS, reactive oxygen species; Nox, NAD(P)H oxidase; eNOS, endothelial NO synthase; mtROS, mitochondrial reactive oxygen species; O2, oxygen; 1O2, singlet oxygen; O2•–, superoxide; SOD, superoxide dismutase; H2O2, hydrogen peroxide; H2O, water; OH·, hydroxyl radical; NO, nitric oxide; ONOO-, peroxynitrite; CAT, catalase; GSH-Px, glutathione peroxidase; NADPH, nicotinamide adenine dinucleotide phosphate.

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  Figure 3. Ang II and mitochondrial dysfunction. Ang II can not only damage mtDNA by stimulating mtROS production in several ways but also damage nDNA directly. MtDNA mutations directly accelerate mitochondrial dysfunction, while nDNA damages result in mitochondrial dysfunction by activating P53 and subsequently inhibiting PGC-1αandPGC−1β, therefore contributing to aging. Besides, Ang II binding to AT1R activates Akt and in turn phosphorylates PGC-1α/β, leading to mitochondrial dysfunction. The mitochondrial ETC is composed of four respiratory complexes (1-IV) and ATP synthase(F0 − 1), which are all made up of proteins encoded by both mitochondrial (purple) and nuclear (pink) genes. MtROS (red asterisk) are primarily generated from complexes I and III in the ETC. mtDNA, mitochondrial DNA; nDNA, nuclear DNA; PGC-1α and PGC-1β, peroxisome proliferator-activated receptor gamma coactivator 1-alpha and -beta; ETC, electron transfer chain; ATP, adenosine triphosphate; Cyt c, cytochrome c; ADP, adenosine diphosphate; NADH, nicotinamide adenine dinucleotide; FAD, flavin adenine dinucleotide; FADH2, flavine adenine dinucleotide reduced; CoQ, Coenzyme Q; TCA, tricarboxylic acid cycle.

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  Figure 4. Ang II and telomere attrition. (A) Shelterin complex, structure of the D-loop and T-loop at the end of telomere. (B) Ang II, telomeres, and senescence. Telomeres are at the ends of linear chromosomes and combine with shelterin multiprotein complexes to escape from DDR. Shelterin complex comprises six diverse protein subunits: TRF1, TRF2, POT1, TIN2, TPP1, and RAP1, and are involved in chromosome end protection, while telomerase is made up of TERT and TR to function as end replication. However, the G-rich chain of telomeric DNA is sensitive to ROS induced by Ang II, and further accumulates 8-oxoG damages and forges high frequency of single-strand breakage in the DNA backbone. Concomitantly, Ang II also reduces telomerase activity by decreasing PGC-1α function. All these eventually accelerate replicative senescence. DDR, DNA damage response; TRF1 and TRF2, telomeric-repeat-binding factor 1 and 2; POT1, protection of telomeres 1; TIN2, TRF1-interacting nuclear protein 2; TPP1, TIN2-interacting protein; RAP1, repressor and activator protein 1; TERT, telomerase reverse transcriptase; TR, telomerase RNA; 8-oxoG, 8-oxo-2-deoxyguanosine.

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  Figure 5. Signaling pathways in telomere attrition and mitochondrial dysfunction during aging. Ang II binding to AT1R reduces the function of PGC-1α via activating Akt, causing the compromises of Sirt1 activity and oxidative defense. Telomere attrition mediates mitochondrial impairment by the p53-dependent downregulation of PGC-1α. Impaired mitochondria generate more mtROS which leads to further telomere attrition and replicative senescence by NF-κB-dependent upregulation of Nox. NF-κB, nuclear factor κB.